Trihydrocarbyl-9-{8 2,6,6-trimethyl-1-cyclohexen-1-yl{9 -3,7-dimethyl-2,6,8-nonatrien-4yene phosphonium halides

ABSTRACT

This invention relates to trihydrocarbyl-9-(2,6,6-trimethyl-1cyclohexen-1-yl)-3,7-dimethyl-2,6,8 nonatrien-4-yne phosphonium halides which are useful as intermediates in the preparation of trans-beta-carotene.

United States Patent [72] Inventor Joseph Donald Surmatis West Caldwell, NJ.

July 16, 1970 Nov. 23, 1971 Hoffmann-La Roche Inc.

Nutley, NJ.

Original application July 1 1, 1968, Ser. No. 743,979, Original application Dec. 4, 1964, Ser. No. 416,128, now Patent No. 3,408,414, dated Oct. 29, 1968. Divided and this application July 16, 1970, Ser. No. 55,582

[21 App]. No. [22] Filed [45] Patented [73] Assignee [54] TRlHYDROCARBYL-9-[2,6,6-TRIMETHYL-l- CYCLOl-[EXEN-l-YL]-3,7-DlMETl-lYL-2,6,8- NONATRIEN-4YENE PHOSPl-IONIUM HALIDE 2 Claims, No Drawings [52] U.S.Cl ..260/606.5 F, 260/666C [51] Int. (1 C07f 9/06, C07c 13/20 [50] Field of Search 260/6065 F, 666 C [56] References Cited UNITED STATES PATENTS 3,294,844 12/1966 Sainecki et al 260/6065 F 3,347,932 10/1967 Chechak 260/6065 F Primary Examiner-Tobias E. Levow Assistant Examiner-Wertcn F. W. Bellamy Attorneys-Samuel L. Welt, Jon S. Saxe, Bernard S. Leon,

William H. Epstein and George M. Gould ABSTRACT: This invention relates to trihydrocarbyl-9- [2,6,6-trimethyl-l-cyclohexen-l-yl1-3 ,7-dimethyl-2,6,8 nonatrien-4-yne phosphonium halides which are useful as intermediates in the preparation of trans-beta-carotene.

1 2 TRlflYDROCARBYL-QJ 2,6,6-TRIME'IHYL 1- DETAILED DESCRIPTION 7 CYCLQH XE .y .3 7 1 ,2 6,8- The process of producing trans-B'carotene from oxenin oi" isooxenin b the recess of this invention is carried out ac- NONATRENAYENE PHOSPHONIUM HALIDES cording to the foll wing reaction scheme.

RELATED APPLICATIONS In the flowsheet belovg X is chlorine or brorni ie Ar is an aryl radical, e.g., phenyl, m0noor dlhydroxy-substltuted This application is a divisional application of Ser. No. phenyl, or monoor di-lower alkyl-substituted phenyl, e.g.,

743,979 filed July 11, 1968, which in turn is adivisional applitolyl, xylyl, etc., and R and R are Ar or higher alkyl, i.e.,

cation of Ser. No. 416,128, filed Dec. 4, 1964, now US. Pat. 10 straight or branched-chain alkyl having eight or more carbon No. 3,408,414. atoms.

CHzOH I A/ /b/ (I) oxenin (II) isooxenin 9-[2,6,6-trimethy1-1- d1methy1-2,6-nonadlen4- (HI) yne-1,8-dlhallde A: l I

PgR I 211; 0):

1 e9/Ar 0 CH2P RX /\/cm;(o 02115): E R1 i +vltamln A /+vitam1n A aldehyde aldehyde (Iii dlar n I Q catalyst) (VI) ll-dehydro-fl-carotene 0 I CH2;(OC:Ho 2

(IX) retinyl dlethyl phosphonate +vitam1n A aldehyde (VII) ll-mono-cis-fl-carotene (VIII) trans-B-carotene In the above reaction scheme oxenin (9-[2,6,6-trimethyl-lcyclohexenl -yl1-3,7-dimethyl-2,6-nonadien-4-ynel ,6-diol) (1) is reacted with a phosphorus trihalide, i.e., phosphorus forms compound III. The above reactions with phosphorus trihalide are preferably carried out in an inert organic solvent,

e.g., a hydrocarbon solvent, such as petroleum ether.

The above dihalide (Ill) can then be condensed with a phosphine of the formula:

wherein Ar is an aromatic hydrocarbon radical, e.g., phenyl, monoor di-lower alkyl-substituted phenyl, such as tolyl, xylyl, etc. monoor dihydroxy phenyl, etc., and R and R, can be Ar groups or can be higher aliphatic hydrocarbon groups, i.e., straight or branched-chain alkyl groups having at least eight carbon atoms. Triphenyl-phosphine is preferred for use in the instant process. This reaction produces a compound of formula IV.

The compound of formula IV is then reacted with vitamin A aldyhyde, preferably in an inert solvent, e.g., an aliphatic hydrocarbon solvent, benzene, etc., or an ether, e.g., tetrahydrofuran, or in pyridine, the latter being the preferred .solvent for use in the practice of the invention, to form lldehydro-fi-carotene (VI). The reaction is carried out in the presence of an alkali metal lower alkoxide, e.g., sodium methoxide. l l-Dehydro-B-carotene (VI) is then hydrogenated in the presence of a palladium catalyst poisoned with lead lsee, e.g., H. Lindlar, Helv. Chirn. Acta, 35, 446 (l952)] preferably in an inert solvent, e.g., an aliphatic hydrocarbon I solvent, to form l l-mono-cis-B-carotene (VII).

ll-Mono-cisfl-carotene is isomerized to trans-fi-carotene (VIII) by heating, e.g., at a temperature in the range of from about 90 to about 95 for from about l to about 20 hours.

Alternatively, compound III above can be reacted with triethoxy phosphite to fonn a phosphonate derivative of formula V. Compound V is then reacted with vitamin A aldehyde under the same conditions given above for compound IV to form ll-dehydro-B-carotene (VI).

Alternatively, compound V can be hydrogenated with a Lindlar catalyst, under the same conditions employed to 'hydrogenate ll-dehydro-fi-carotene (VI) to ll-mono-cis-B- carotene (VII). Retinyl diethyl phosphonate (IX) is formed thereby. Retinyl diethyl phosphonate is then reacted with Vitamin A aldehyde, under the same conditions employed above with compound IV, to yield trans-fl-carotene (VIII).

Isooxenin (II) is a novel compound which is obtained by reacting 3-hydroxy-3-methyl-penten-l-yne-4 with methyl EXAMPLE I Preparation of 9-[2,6,6-trimethyl-l-cyclohexen-l-yl1-3 ,7- dimethyl-2,6-nonadien-4-ynel ,8-halide Oxenin 9-[2,6,6-trimethyll -cyclohexenl -yl 1-3 ,7- dimethyl-2,7-nonadien-4-ynel ,6-diol) (400 g.) was placed in .a -liter flask with 2,000 ml. of ethyl ether and 5 ml. of

pyridine. Phosphorus tribromide (128 ml.) was dissolved in petroleum ether (800 ml.) and added to the stirred reaction at 5 over 3 hours. The reaction mixture was poured onto crushed ice in a separator, and the ether layer containing the product was separated. This was washed with water, saturated sodium bicarbonate solution, and finally with water. After drying over anhydrous sodium sulfate, the solvent was removed under vacuum, with a temperature not exceeding 30. The product, 9-[2,6,6-trimethyll -cyclohexenl -yl 1-3 ,7-dimethyl- 2,6-nonadrien4-yne-l ,8-halide, which was obtained as a dark orange colored syrup, weighed 497 g. and the ultraviolet adsorption had a maximum at 287 a (in ethanol).

EXAMPLE 2 Preparation of triphenyl-9-[2,6,6-trimethyll -cyclohexenel yl1-3,7-dimethyl-2,6,8-nonatrien-4-yne phosphonium bromide l40 g. of 9-[2,6,6-trimethyl-l-cyclohexen-l-yl]-3,7- dimethyl-2,6-nonadien-4-yne-l,8-halide, 1,000 ml. of tetrahydrofuran, and l67 g. of triphenyl-phosphine were placed in a 2-liter flask and stirred under an atmosphere of nitrogen for 48 hours. The ultraviolet adsorption spectrum was detennined on a sample of the reaction mixture and was found to have a maximum at 330;:.. This was used for the next step without further purification.

EXAMPLE 3 Preparation of l l-dehydro-ficarotene A methanol solution of sodium methoxide (prepared by dissolving l6 g. of sodium in 500 ml. of methyl alcohol) and a second solution consisting of 77 g. of vitamin A aldehyde dissolved in 500 ml. of methyl alcohol, were charged to separate dropping funnels and added at the same time to the reaction product from example 2. The addition required I hour. The stirring was then continued for an additional 2 hours under an atmosphere of nitrogen. The reaction mixture was placed in a separator with 1 liter of water and extracted with methylene chloride. On removal of the solvent under vacuum, the product consisted of crude ll-dehydro-B-carotene. The ultraviolet spectrum showed the main adsorption maximum at 427p. with an inflection at 455 p. (in cyclohexane). Afler purification from methylene chloride-methanol, the product was obtained as an orange colored crystalline solid with E 1,800 at 427 (in cyclohexane).

EXAMPLE 4 Preparation of l l-mono-cis-u-carotene A solution of l l-dehydro-u-carotene prepared according to example 3 l0 g.) in n-heptane (200 ml.) was hydrogenated in the presence of 0.5 g. of a lead-poisoned palladium catalyst prepared by adding 3.5 parts of lead acetate to 4| parts of palladium chloride precipitated on calcium carbonate (5 percent palladium chloride) until a one-molar equivalent of hydrogen was consumed. The catalyst was filtered off under an atmosphere of nitrogen, and washed with additional n-heptane. 0n removal of the solvent. the product consisted of crude l lmono-cis-B -carotene with ultraviolet adsorption maxima at 335, 454, and 48011..

EXAMPLE 5 Preparation of trans-B-carotene The ll-mono-cis-fi-carotene prepared according to example 4 was placed in a flask with 20 ml. of heptane and stirred under an inert atmosphere for 20 hours at C. This caused the ciscarotene to isomerize to the trans form which began to crystallize from the hot heptane. The reaction was cooled to room temperature, filtered, and the product on the filter, which consisted of almost pure trans-B-carotene, was washed with additional heptane and dried under vacuum. The product has E 2,219 at 45411.. On recrystallization from methylene chloride, pure trans-,B-carotene was obtained with E 2,450 at 454p. (in cyclohexane).

EXAMPLE 6 Preparation of diethyl 9-[2,6,6-trimethyl-l-cyclohexen-l-yl1- 3,7-dimethyl-2,6,8-nonatrien-4-yne phosphonate 214 g. of 9-[2,6,6-trimethyl-l-cyclohexen-l-yl]-3,7- dimethyl-2,6-nonadien-4-yne-1,8-halide prepared according to example I, was placed in a flask with 166 g. of triethyl phosphite. The flask was fitted with a condenser for distillation and the contents were slowly heated to 140 over a period of 2 hours. Most of the reaction took place between 120 and l40while a distillate which was rich in ethyl bromide was collected. The heating was then continued for an additional hour allowing the temperature to rise to 150.

The lower boiling impurities were removed under vacuum by heating to l20 at 10 mm. There was obtained 216 g. of crude diethyl-9-[ 2,6,6-trimethyll -cyclohexenl -yl ]-3,7- dimethyl-2,6,8-nonatrien4-yne phosphonate with u 1.5612. A pure analytical sample was prepared by distillation through a molecular still. This had a boiling point of 1 10 at 10 microns with n 1.5644. The ultraviolet adsorption spectrum had a maximum at 318 (in ethyl alcohol).

EXAMPLE 7 Preparation of l l-dehydro-B-carotene 8 g. of diethyl 9-[2,6,6-trimethyl-l-cyclohexen-l-yl]-3,7- dimethyl-2,6,8-nonatrien-4-yne phosphonate prepared according to example 6, was dissolved in 100 m1. of tetrahydrofuran. Vitamin A aldehyde g.) and solid sodium. methoxide (1.5 g.) were added in the order named. The reaction was stirred under an atmosphere of nitrogen for 4 hours.

The reaction mixture was diluted with 200 ml. of water and extracted with methylene chloride. After removal of the methylene chloride, the product consisted of ll-dehydro-B- carotene (which was also obtained by example 3 The product, after purification from methylene chloride and methyl alcohol, was obtained as an orange colored crystalline solid with E, m 1,850 at 427 B.

EXAMPLE 8 One mole of ethyl magnesium bromide in 500 ml. of ethyl ether was prepared by the usual Grignard procedure in a 2- liter round-bottom flask. 3-Hydroxy-3-methylpenten-l-yne-4 (48 g.) was placed in a separatory funnel with an equal volume of ethyl ether and added to the Grignard reagent over a period of 2 hours. After stirring for an additional 10 minutes, 103 g. of C aldehyde (4-[2,6,6-trimethylcyclohexen-l-yl]-2- methyI-Z-buten-l-al) was charged to the separatory funnel and added while stirring vigorously in 1 hour. After all of the aldehyde was added, the reaction flask was warmed externally to cause the ether to reflux while stirring for 2 additional hours.

The reaction was decomposed with water and most of the resulting grey precipitate was dissolved in 5 percent sulfuric acid. The ether layer was separated and water washed. On removal of the ether solvent, a white crystalline mass was ob tained. To this there was added 200 ml. of petroleum ether. The solid mass was broken up, and the petroleum ether was heated to reflux while stirring. The solubility of the isooxenin was such that most of it remained undissolved. This was cooled overnight in a refrigerator and filtered. There was obtained 121 g. of dried isooxenin, melting point 102.

EXAMPLE 9 Preparation of 9-[ 2,6,6-trimethyll -cyclohexenl -yl ]-3,7- dimethyl-2,6-nonadien-4-ynel ,8-halide 33 g. of isooxenin which was prepared according to example 8, was placed in a flask with 200 ml. of ethyl ether and 4 drops of pyridine. Phosphorous tribromide l 1 ml.) was dissolved in 50 ml. of hexane and dropped into the stirred reaction at 5 in 1 hour. The reaction mixture was poured onto crushed ice in a separator. The ether layer was separated, washed with water, saturated sodium bicarbonate solution, and finally with water. The solution was dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The product was obtained as an orange colored syrup, with the violet adsorption maximum at 287p. (in ethanol). This product, 9-[2,6,6- trimethyll -cyclohexe nl -yl ]-3 ,7-dimethyl-2,6-nonadien-4- ynel ,8-halide, was identical with the compound prepared according to example 1.

EXAMPLE 10 Preparation of retinyl diethyl phosphonate A solution of diethyl 9-[ 2,6,6trimethyl-l-cyclohexenl -yl]- 3,7-dimethyl-2,6,8-nonatrien-4yne phosphonate (12 g.) in toluene (240 ml.) was hydrogenated in the presence of poisoned palladium catalyst (H. Lindlar, l-lelv. Chim. Acta, 35, 446 1952)] until a one-molar equivalent of hydrogen was consumed. The catalyst was filtered off and washed with toluene. Upon removal of the solvent under vacuum, the product, which was retinyl diethyl phosphonate, was obtained as an orange colored syrup with n 25 2.555. This was employed in the next step without further purification.

EXAMPLE 1 1 Preparation of trans-B-carotene Retinyl diethyl phosphonate (10 g.), vitamin A aldehyde (7 g.) and sodium methoxide (1.5 g.) were added to ml. of

vtetrahydrofuran in the order named and the reaction was stirred under an atmosphere of nitrogen for 4 hours.

The resulting dark red solution was poured into water and extracted with methylene chloride. On removal of the solvent, the residue consisted of a mixture of trans and l l-mono-cis-B- carotene.

The crude carotene mixture was placed in a flask with 20 ml. of heptane and refluxed for 20 hours under an atmosphere of nitrogen. This was cooled, diluted with additional heptane and filtered to give almost pure trans-B-carotene in high yield. On recrystallization from methylene chloride, pure trans-[3- carotene was obtained, melting point l82E"*, m (454p) 2450 (in cyclohexane).

We claim: 1. A compound of the formula:

/Ar cmr-rtx Q R1 wherein Ar is an aryl radical; R and R, are selected from the group consisting of higher alkyl and Ar and X are selected from the group consisting of chlorine and bromine.

2. A compound in accordance with claim 1 wherein said compound has the formula: 

2. A compound in accordance with claim 1 wherein said compound has the formula: 